Compositions for treatment of muscular disorders

ABSTRACT

The present invention relates to a pharmaceutical composition for prevention or treatment of a muscular disease, the composition comprising dimenhydrinate, harmol and/or calcium pantothenate as active ingredients. Application of dimenhydrinate, harmol, and calcium pantothenate individually has an effect of promoting myoblast proliferation and differentiation. In particular, the combination thereof has the effect of synergistically increasing the effect of promoting myoblast proliferation and differentiation. Thus, dimenhydrinate, harmol and/or calcium pantothenate may be usefully used alone or in combination for the prevention or treatment of muscular diseases, in particular sarcopenia.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a § 371 National Stage of International ApplicationNo. PCT/KR2019/004631 filed Apr. 17, 2019, claiming priority to KoreanPatent Application No. 10-2018-0047957 filed Apr. 25, 2018.

TECHNICAL FIELD

The present disclosure relates to a pharmaceutical composition fortreatment of a muscular disease. More particularly, the presentdisclosure relates to a pharmaceutical composition for preventing ortreating a muscular disease, the composition comprising dimenhydrinate,harmol and/or calcium pantothenate as an active ingredient.

BACKGROUND ART

A skeletal muscle makes up the largest part of the human body, andaccounts for 40 to 50% of a total body weight and plays an importantrole in various metabolic functions in the body, including energyhomeostasis and heat generation. An amount of a human muscle decreasesby more than 1% annually after an age 40 and then to a 50% of a maximummuscle amount at an age 80. This muscle loss in the old age isrecognized as the most important factor that impairs overall physicalfunctions. As the aging progresses, a muscle and fat content changes anda skeletal distortion occurs. A prevalence of an obesity due to thereduction of the muscle amount in the old age has been continuouslyincreasing from 30% worldwide. Abnormal insulin secretion may cause amuscle development disorder due to poor energy supply to cells, suchthat sarcopenia increases in patients having diabetes mellitus comparedto a normal person. In addition, a decrease in muscle causes morearthritis, back pain, chronic pain and causes urinary incontinencecaused by abdominal obesity to be worsen. Fracture injuries may lead toincreased depression in an old age, leading to death. Thus, sarcopeniain the old age is associated with various diseases and thus is a majorcause of poor quality of life.

The sarcopenia refers to a condition in which the amount and function ofa skeletal muscle are reduced. The sarcopenia is caused by a variety ofcauses, including aging, hormonal abnormalities, malnutrition, lack ofphysical activity, inflammatory and degenerative diseases. Among them,cancer, aging and sex hormone deficiency are known to be a major causeof the sarcopenia. Due to the development of medical technology and thedevelopment of various treatment agents, the aging population isincreasing as life expectancy increases. Accordingly, the demand fortreatment of sarcopenia is expected to increase continuously. Inpatients with sarcopenia, the number of myoblasts decreases due todisorder of gathering, activity or proliferation of satellite cells asstem cells of myoblasts, and a decrease in myoblast proliferation anddifferentiation occurs. As a result, the muscle of the patient havingsarcopenia has a decrease in the size and number of muscular fibers at ahistological level, leading to decreased muscle function. In the pastdecade, research on the epidemiology of sarcopenia has been activelyconducted in the United States and Europe. Then, the interest in theclinical significance of sarcopenia has recently increased. Earlystudies have shown that sarcopenia causes poor quality of life due tosystemic weakness, impaired activity and decreased muscle strength.Recent studies have reported that sarcopenia causes a significantincrease in the risk of osteoporotic fractures in addition to thedeterioration of the quality of life. Further, in sarcopenia patients,chronic diseases such as diabetes and metabolic syndrome, obesity,chronic renal failure, chronic liver failure, etc. are developed,leading to the increased mortality. Thus, sarcopenia is of interest as adisease that must be treated properly. Recently, it is reported in theUnited States that a 1.5 to 3.5-fold increase in the likelihood ofdeveloping physical disabilities in sarcopenia patients occurs,resulting in $ 18.5 billion in social costs per year. In Korea,according to the National Health and Nutrition Survey, the prevalence ofsarcopenia is 42.0% for males and 42.7% for females over 60 years old.In particular, as Korea has the fastest aging rate in the world, it iscertain that the sarcopenia will be a significant social problem in thefuture.

Cancer-induced sarcopenia is caused by malnutrition, lack of exerciseand cytokines secreted by cancer such that muscle mass and physicalfunction are significantly reduced. According to statistics, sarcopeniacaused by cancer is found in 14 to 78.7% of all cancer patients.According to statistics, sarcopenia caused by cancer is found in morethan 50% of patients of cancers of a digestive system and in about 40%of patients of lung cancer and liver cancer. According to a recentreport from the European Cancer Center, patients with esophageal cancerhaving sarcopenia had an average of 2 years and 8 months of shorteningof life expectancy and showed an increase in complications of cancersurgery compared to patients with esophageal cancer without sarcopenia.According to a Japanese cancer center report, the number of patients whosurvived without cancer reoccurrence for five years after liver cancersurgery is doubled in the absence of sarcopenia compared to the presencethereof. Thus, sarcopenia may affect the cancer recurrence. In patientswith sarcopenia, anticancer drug discontinuation and dose reduction alsooccur more frequently than in patients without sarcopenia, Thus, thesarcopenia affects an overall survival percentage. Thus, sarcopenia maybe a bad factor that greatly affects the overall survival of the cancerpatients. There is a need for a solution for sarcopenia.

Sarcopenia caused by degeneration of spinal nerve, motor nerve orskeletal muscle fibers associated with muscle disease is one ofrepresentative refractory diseases for which a causing factor has notyet been identified. So far, research has shown that the motor nervesthat induce skeletal muscle contraction degenerate such that contractionof the skeletal muscle does not progress, or the expression of proteinsinvolved in muscle contraction in the skeletal muscle is reduced or theprotein is modified so that normal skeletal muscle contraction does notproceed, and in the long term, the motor nerve or skeletal muscle istransformed into fibrous tissue. The underlying cause of sarcopenia hasnot yet been identified. No method has been developed to prevent motorneuron or skeletal muscle degeneration or recover the motor neuron orskeletal muscle. Thus, at present, studies are being actively conductedto develop a method for slowing the progress of sarcopenia. Currently,exercise, protein and calorie supplements are known to help withreduction of sarcopenia. For the elderly, who make up the majority ofsarcopenia patients, the exercise, protein and calorie supplements arenot very helpful. Thus, a treatment agent of sarcopenia is urgentlyrequired. However, for the drugs currently used for sarcopenia, a drughaving a direct effect on reducing the muscle loss and increasing musclemass is still at the stage of clinical experiments. Currently, no drugis finally approved by the FDA. There are efforts to develop, as atreatment agent of sarcopenia, selective androgen receptor modulators,activin receptor antagonists, and fast skeletal muscle troponininhibitors to treat the sarcopenia. However, those are currently at theinitial clinical trial. Currently, a method of treating sarcopeniaincludes a method of suppressing muscular atrophy caused by degenerationor progressive mutation of muscle cells, which is a kind of sarcopenia.For example, WO 2007/088123 discloses a therapeutic agent for muscularatrophy, which contains a nitrooxy derivative as an active ingredient.WO 2006/081997 discloses a therapeutic agent for muscular atrophy, whichcontains an atraric acid or a derivative thereof as an activeingredient. However, these therapeutic agents comprising compounds asactive ingredients act not only on skeletal muscles in which muscularatrophy is developed, but also on visceral or myocardium that is notassociated with muscular atrophy. Thus, various side effects may becaused. Thus, the above agents are not used for practical treatment. Onthe other hand, hormonal preparations have significantly lowered sideeffects than compound preparations and the hormonal preparations arebio-friendly. Thus, the development of drugs for treating muscularatrophy or sarcopenia using hormonal preparations is being accelerated.

According to reports on sarcopenia treatment trends, the globalsarcopenia treatment market in 2010 amounted to approximately $ 10million (US) and grows to $ 20 million in 2018 (“SarcopeniaTherapeutics-Pipeline Assessment and Market Forecasts to 2018”, Nov. 17,2011). Further, in 2013, the EU Innovative Meticines Initiative as aprivate custody partnership under the EU announced an ongoing investmentof approximately 50 million euros for the development of the elderlysarcopenia treatment as one of the four major health research topics.

DISCLOSURE Technical Problem

The present inventors have identified from finding preventive andtherapeutic substances for muscular disease, that dimenhydrinate, harmolor calcium pantothenate has therapeutic effects on muscular disease,especially sarcopenia, and a combination thereof has a synergy effect.Thus, the present disclosure was completed.

Technical Solution

In order to achieve the above object, the present disclosure provides apharmaceutical composition for prevention or treatment of a musculardisease, the composition comprising dimenhydrinate, harmol or calciumpantothenate as an active ingredient.

Further, the present disclosure provides a pharmaceutical compositionfor the prevention or treatment of muscle and fat loss due toadministration of an anticancer drug, the composition comprisingdimenhydrinate or calcium pantothenate as an active ingredient.

In addition, the present disclosure provides a food composition forprevention or amelioration of a muscular disease, the compositioncomprising dimenhydrinate, harmol or calcium pantothenate.

Advantageous Effects

Dimenhydrinate, harmol and calcium pantothenate in accordance with thepresent disclosure alone have an effect of promoting the proliferationand differentiation of myoblasts. In particular, the combination ofthese has an effect of synergistically increasing the proliferation anddifferentiation promoting effects of myoblast. Thus, the dimenhydrinate,harmol and calcium pantothenate may be usefully used for the preventionor treatment of the muscular disease alone or in combinations thereof.The dimenhydrinate, harmol and calcium pantothenate may also be used toprevent or treat the muscle and fat loss caused by anticancer drugs.

DESCRIPTION OF DRAWINGS

FIG. 1 is a photograph and graph showing the effect of promotingmyoblast proliferation by dimenhydrinate (OC-501) application accordingto the present disclosure.

FIG. 2 is photographs identifying the differentiation-promoting effectsof myoblasts by dimenhydrinate applications according to the presentdisclosure:

Upper: 4× magnification image after differentiation; and

Lower: 10× magnification image after differentiation.

FIG. 3 shows a Western blot analysis of the expression level of musclecell differentiation markers myogenin and MHC (myosin heavy chain).

FIG. 4 is a photograph and graph showing the effect of promotingmyoblast proliferation by harmol (OC-503) application according to thepresent disclosure.

FIG. 5 is photographs showing the differentiation-promoting effects ofmyoblasts caused by the harmol application according to the presentdisclosure:

Upper: 4× magnification image after differentiation; and

Lower: 10× magnification image after differentiation.

FIG. 6 shows the Western blot analysis of the expression levels ofmuscle cell differentiation markers myogenin and MHC (myosin heavychain).

FIG. 7 is a photograph and graph showing the effect of promotingmyoblast proliferation by calcium pantothenate (OC-504) applicationaccording to the present disclosure.

FIG. 8 is photographs identifying the differentiation-promoting effectsof myoblasts by calcium pantothenate application according to thepresent disclosure:

Upper: 4× magnification image after differentiation; and

Lower: 10× magnification image after differentiation.

FIG. 9 shows the level of expression of muscle cell differentiationmarkers myogenin and MHC (myosin heavy chain) by Western blot analysis.

FIG. 10 shows the cytotoxicity to myoblasts when a combination ofdimenhydrinate, harmol and calcium pantothenate is applied.

FIG. 11 shows the effect of increasing myoblast proliferation when acombination of dimenhydrinate and harmol or calcium pantothenate isapplied.

FIG. 12 shows the effect of increasing myoblast proliferation when acombination of dimenhydrinate and harmol or calcium pantothenate isapplied.

FIG. 13 shows the effect of increasing myoblast proliferation when acombination of harmol and calcium pantothenate, and a combination ofdimenhydrinate, harmol and calcium pantothenate are applied.

FIG. 14 shows the differentiation effects of myoblasts when acombination of dimenhydrinate and harmol or calcium pantothenate isapplied:

Upper: 4× magnification image after differentiation; and

Lower: 10× magnification image after differentiation.

FIG. 15 shows the level of differentiation of myoblast via theexpression level of myogenin and MHC as muscle cell differentiationmarkers in the application of a combination of dimenhydrinate and harmolor calcium pantothenate.

FIG. 16 shows the effects of promoting myoblast differentiation bymicroscopic and western blot analysis when calcium pantothenate isapplied and when a combination of dimenhydrinate and calciumpantothenate is applied.

FIG. 17 shows the effect of muscle regeneration via an application ofthe combination of dimenhydrinate and calcium pantothenate.

FIG. 18 shows the effect of early recovery of muscle fibers via theapplication of the combination of dimenhydrinate and calciumpantothenate.

FIG. 19 shows the course of causing cancer-associated sarcopenia and theschedule of administration of the dimenhydrinate and calciumpantothenate therefor.

FIG. 20 shows the effects of cancer-associated muscle and fat reductionvia the application of the combination of dimenhydrinate and calciumpantothenate.

MODES OF THE INVENTION

Hereinafter, exemplary embodiments of the present disclosure will bedescribed in detail with reference to the accompanying drawings.However, the following embodiments are presented as an example of thepresent disclosure. When it is determined that the detailed descriptionof the well-known technology or construction known to those skilled inthe art may unnecessarily obscure the subject matter of the presentdisclosure, detailed descriptions thereof will be omitted. The presentdisclosure may be subjected to various modifications and applicationswithin the scope of the following claims and their equivalents.

The terminology used herein is for the purpose of describing particularembodiments only and is not intended to be limiting of the presentdisclosure. This may vary depending on the intention of the user, theoperator, or customs in the field to which the present inventionbelongs. Therefore, the definitions of the terms should be made based onthe contents throughout the specification. It will be further understoodthat the terms “comprises”, “comprising”, “includes”, and “including”when used in this specification, specify the presence of the statedfeatures, integers, operations, elements, and/or components, but do notpreclude the presence or addition of one or more other features,integers, operations, elements, components, and/or portions thereof.

Unless otherwise defined, all terms including technical and scientificterms used herein have the same meaning as commonly understood by one ofordinary skill in the art to which this inventive concept belongs. Itwill be further understood that terms, such as those defined in commonlyused dictionaries, should be interpreted as having a meaning that isconsistent with their meaning in the context of the relevant art andwill not be interpreted in an idealized or overly formal sense unlessexpressly so defined herein. Although described herein are preferredmethods or samples, equivalent thereto are included in the category ofthe present disclosure. The contents of all publications incorporatedherein by reference are incorporated into the present disclosure.

In one aspect, the present disclosure relates to a pharmaceuticalcomposition for the prevention or treatment of muscular diseases, thecomposition comprising dimenhydrinate, harmol or calcium pantothenate asan active ingredient.

In one implementation, the dimenhydrinate may include a compound ofmolecular formula C₂₄H₂₈ClN₅O₃ and molecular weight 469.97 g/mol, asrepresented by a following Chemical Formula 1:

In one implementation, the harmol may include a compound of molecularformula C₁₂H₁₀N₂O and a molecular weight of 198.225 g/mol as representedby a following Chemical Formula 2:

In one implementation, the calcium pantothenate may refer to a calciumsalt of water-soluble vitamin B5, and may include a compound ofmolecular formula C₁₈H₃₂CaN₂O₁₀ and molecular weight 476.536 g/mol asrepresented by a following Chemical Formula 3:

In one implementation, the calcium pantothenate may comprise vitamins.The vitamin may include a water-soluble vitamin selected from the groupconsisting of vitamin C, vitamin B1, vitamin B2, vitamin B6, vitamin H,vitamin PP or pro-vitamin B5 or mixtures thereof. The vitamin mayinclude a fat-soluble vitamin selected from the group consisting ofvitamin A, vitamin D, vitamin E, vitamin K1 or carotene or mixturesthereof. In a more preferred example, the vitamin may include vitamin B2(riboflavin, vit B2).

In one implementation, each of dimenhydrinate, harmol and calciumpantothenate may be contained in a content range of from 250 nM to 20μM. More preferably, the harmol may be contained in a content range of500 nM to 10 μM and the calcium pantothenate may be contained in acontent range of 500 nM to 20 μM.

In one implementation, the pharmaceutical composition according to thepresent disclosure may contain a combination of dimenhydrinate andharmol, a combination of dimenhydrinate and calcium pantothenate, acombination of harmol and calcium pantothenate, or a combination ofdimenhydrinate, harmol and calcium pantothenate as an active ingredient.In one example, the pharmaceutical composition according to the presentdisclosure may contain combinations of dimenhydrinate, harmol and/orcalcium pantothenate as follows: dimenhydrinate 5 μM+harmol 250 nM,dimenhydrinate 5 μM+harmol 500 nM, dimenhydrinate 5 μM+calciumpantothenate 5 μM, dimenhydrinate 5 μM+calcium pantothenate 10 μM,dimenhydrinate 10 μM+harmol 250 nM, dimenhydrinate 10 μM+harmol 500 nM,dimenhydrinate 10 μM+calcium pantothenate 5 μM, dimenhydrinate 10μM+calcium pantothenate 10 μM, harmol 250 nM+calcium pantothenate 5 μM,harmol 250 nM+calcium pantothenate 10 μM, harmol 500 nM+calciumpantothenate 5 μM, harmol 500 nM+calcium pantothenate 10 μM,dimenhydrinate 5 μM+harmol 250 nM+calcium pantothenate 5 μM,dimenhydrinate 5 μM+harmol 250 nM+calcium pantothenate 10 μM,dimenhydrinate 10 μM+harmol 250 nM+calcium pantothenate 5 μM,dimenhydrinate 10 μM+harmol 250 nM+calcium pantothenate 10 μM,dimenhydrinate 5 μM+harmol 500 nM+calcium pantothenate 5 μM,dimenhydrinate 5 μM+harmol 500 nM+calcium pantothenate 10 μM,dimenhydrinate 10 μM+harmol 500 nM+calcium pantothenate 5 μM, anddimenhydrinate 10 μM+harmol 500 nM+calcium pantothenate 10 μM. In apreferable example, the pharmaceutical composition according to thepresent disclosure may contain combinations of dimenhydrinate, harmoland/or calcium pantothenate as follows: dimenhydrinate 10 μM+calciumpantothenate 5 μM, dimenhydrinate 10 μM+calcium pantothenate 10 μM,harmol 250 nM+calcium pantothenate 5 μM, and harmol 250 nM+calciumpantothenate 10 μM.

In one implementation, the muscular disease may include a musculardisease due to muscular dysfunction, muscle loss or muscle degenerationand may include one or more selected from a group consisting of atony,muscular atrophy, muscular dystrophy, myasthenia, cachexia andsarcopenia. More preferably, the muscular disease may include sarcopeniadue to aging or cancer.

In one implementation, dimenhydrinate, harmol and/or calciumpantothenate in accordance with the present disclosure may increasemuscle mass or muscle strength or improve muscle function via thepromotion of myoblast proliferation and differentiation.

In one implementation, dimenhydrinate, harmol and/or calciumpantothenate in accordance with the present disclosure may prevent ortreat muscle or fat loss due to anticancer treatment.

In one implementation, the anticancer treatment may involve in one ormore selected from a group consisting of anticancer agents,chemotherapeutic agents, immunotherapy agents, antibacterial agents,radiotherapy agents and antiviral agents, and photodynamic therapy. Theanticancer agent may be 5-FU (5-fluorouracil).

The composition in accordance with the present disclosure contains notonly dimenhydrinate, harmol and calcium pantothenate represented by theChemical Formulas 1 to 3, but also pharmaceutically acceptable saltsthereof, and possible solvates, hydrates, racemates or stereoisomersthat may be prepared therefrom.

Dimenhydrinate, harmol and calcium pantothenate as represented byChemical Formulas 1 to 3 according to the present disclosure may be usedin the form of pharmaceutically acceptable salts. The salts may be acidaddition salts formed with pharmaceutically acceptable free acids. Acidaddition salts may include inorganic acids such as hydrochloric acid,nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid,hydroiodic acid, nitrous acid or phosphorous acid, non-toxic organicacids such as aliphatic mono and dicarboxylates, phenyl-substitutedalkanoates, hydroxy alkanoates and alkanedioates, aromatic acids,aliphatic and aromatic sulfonic acids. Such pharmaceutically non-toxicsalts may include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite,nitrate, phosphate, monohydrogen phosphate, diaidogen phosphate,metaphosphate, pyrophosphate chloride, bromide, iodide, fluoride,acetate, propionate, decanoate, caprylate, acrylate, formate,isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate,succinate, suberate, sebacate, fumarate, maleate, butine-1,4-dioate,hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate,benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate,xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate,citrate, lactate, hydroxybutyrate, glycolate, malate, tartrate,methanesulfonate, propanesulfonate, naphthalene-1-sulfonate,naphthalene-2-sulfonate or mandelate.

Acid addition salts according to the present disclosure may be preparedby conventional methods, for example, by dissolving dimenhydrinate,harmol and calcium pantothenate as represented by Chemical Formulas 1 to3 in an excess of aqueous solution of acid, and by precipitation of thesalts with a water-miscible organic solvent such as methanol, ethanol,acetone or acetonitrile. Further, the acid addition salts according tothe present disclosure may be prepared by evaporation of solvents orexcess acid from the mixture and drying the mixture, or byabsorbing-filtration of the precipitated salts.

Further, bases may be used to produce the pharmaceutically acceptablemetal salts. Alkali metal or alkaline earth metal salts may be prepared,for example, by dissolving the compound in an excess of alkali metalhydroxide or alkaline earth metal hydroxide solution, and filteringnon-dissolved compound salts, and evaporating and drying the filtrate.In this case, it is pharmaceutically suitable to prepare sodium,potassium or calcium salts as the metal salt. Further, the correspondingsilver salt may be obtained by reacting an alkali or alkaline earthmetal salt with a suitable silver salt (e.g. silver nitrate).

The pharmaceutical composition according to the present disclosure mayfurther contain known muscular disease therapeutic agents in addition todimenhydrinate, harmol and calcium pantothenate as active ingredients.The pharmaceutical composition according to the present disclosure maybe combined with other treatment agents known for the treatment of themuscular diseases.

In one aspect, the present disclosure relates to a pharmaceuticalcomposition for the prevention or treatment of muscle and fat losscaused by anticancer drugs, the composition comprising dimenhydrinate orcalcium pantothenate as an active ingredient.

As used herein, the term “prevention” means any action that inhibits ordelays the occurrence, spread and recurrence of the muscular disease byadministration of the pharmaceutical composition according to thepresent disclosure. As used herein, the term “treatment” means anyaction that reduces or beneficially alters the symptoms of the musculardisease by administration of one or more selected from the groupconsisting of dimenhydrinate, harmol, and calcium pantothenate, or apharmaceutically acceptable salt thereof, or a composition comprisingthe same according to the present disclosure. The person having ordinaryknowledge in the technical field to which the present disclosure belongsrefers to the materials presented by the Korean Medical Association,etc. to determine the exact criteria of the disease on which thecomposition according to the present disclosure will act effectively andto determine the extent of reduction, improvement and treatment thereof.

As used herein, the term “therapeutically effective amount” as used incombination with an active ingredient means an amount effective toprevent or treat a subject disease. The therapeutically effective amountof the composition according to the present disclosure may varydepending on several factors, such as the method of administration, thesite of destination, and the condition of the patient. Therefore, whenused in humans, the dosage should be determined in an appropriate amountin consideration of both safety and efficiency. It is possible toestimate the amount used in humans from the effective amount determinedfrom the animal testing. Considerations in determining the effectiveamount are described, for example, in a following document: Hardman andLimbird, eds., Goodman and Gilman's The Pharmacological Basis ofTherapeutics, 10th ed. (2001), Pergamon Press; and E. W. Martin ed.,Remington's Pharmaceutical Sciences, 18th ed. (1990), Mack PublishingCo.

The pharmaceutical composition according to the present disclosure isadministered in a pharmaceutically effective amount. As used herein, theterm “pharmaceutically effective amount” means an amount sufficient totreat the disease that does not cause side effects at a reasonablebenefit/risk ratio applicable to medical treatment. The effective doselevel may be determined based on the patient's condition, the type ofmuscular disease, the cause of the muscular disease, the severity, theactivity of the drug, the sensitivity to the drug, the method ofadministration, the time of administration, the route of administrationand the rate of release, duration of treatment, drugs for combination orconcurrent use, or other factors well known in the medical arts. Thecomposition according to the present disclosure may be administered asan individual therapeutic agent or in combination with other therapeuticagents and may be administered sequentially or simultaneously with aconventional therapeutic agent and may be administered in a single doseor multiple doses. It is important to administer an amount that willachieve the maximum effect with a minimum amount without side effects,with taking all of the above factors into consideration. The amount maybe readily determined by one skilled in the art.

The pharmaceutical compositions according to the present disclosure maycomprise carriers, diluents, excipients or combinations of two or morecommonly used in biological products. As used herein, the term“pharmaceutically acceptable” refers to being non-toxic to cells orhumans exposed to the composition. The carrier is not particularlylimited as long as the carrier is suitable for in vivo delivery of thecomposition. For example, the carrier may employ a compound recited inMerck Index, 13th ed., Merck & Co. Inc., saline solution, sterile water,Ringer's solution, buffered saline solution, dextrose solution,maltodextrin solution, glycerol, ethanol and a mixture of at least twoof these components. If desired, other conventional additives such asantioxidants, buffers, fungistats, and the like may be added to thecomposition. Further, diluents, dispersants, surfactants, binders andlubricants may be additionally added to the composition to formulate thecomposition into injectable formulations, such as aqueous solutions,suspensions, emulsions and the like, pills, capsules, granules ortablets. Furthermore, the composition may be preferably formulated basedon each disease or component using a suitable method in the art or usinga method disclosed in Remington's Pharmaceutical Science (MackPublishing Company, Easton Pa., 18th, 1990).

In one implementation, the pharmaceutical composition may be prepared inone or more formulations selected from the group consisting of oralformulations, external application preparations, suppositories, sterileinjectable solutions and sprays. In a more preferred example, thepharmaceutical composition may be prepared in oral or injectableformulations.

As used herein, the term “administration” means provision of apredetermined substance to an individual or patient in any suitable way.Depending on the method as desired, the substance may be administerednon-orally (for example, applied as an injectable formulationintravenously, subcutaneously, intraperitoneally or topically) ororally. Dosage may vary according to the patient's weight, age, sex,health condition, diet, time of administration, method ofadministration, rate of excretion and severity of disease. Liquidpreparations for oral administration of the composition according to thepresent disclosure include suspensions, solutions, emulsions, andsyrups. Various excipients, such as wetting agents, sweeteners,fragrances, preservatives, etc., in addition to the commonly used simplediluents, water and liquid paraffin may be contained in the composition.Preparations for parenteral administration include sterile aqueoussolutions, non-aqueous solvents, suspensions, emulsions, lyophilizedpreparations, suppositories, and the like. The pharmaceuticalcomposition according to the present disclosure may be administered byany device that allows the active substance to migrate to the targetcell. Preferred modes of administration and preparations may includeintravenous, subcutaneous, intradermal, intramuscular, drip injectablesand the like. The injectables may be prepared using aqueous solventssuch as physiological saline solution and ringers solution, vegetableoils, higher fatty acid esters (e.g., ethyl oleate, etc.), non-aqueoussolvents such as alcohols (e.g., ethanol, benzyl alcohol, propyleneglycol, glycerin, etc.). The injectables may contain stabilizers toprevent alteration (e.g. ascorbic acid, sodium bisulfite, sodiumpyrosulfite, BHA, tocopherol, EDTA, etc.), emulsifiers, a pharmaceuticalcarrier such as a buffer for adjusting pH, a preservative for inhibitingmicrobial growth (e.g., phenyl mercury nitrate, thiomersal, benzalkoniumchloride, phenol, cresol, benzyl alcohol, etc.).

As used herein, the term “individual” means all animals includingmonkeys, cows, horses, sheep, humans, pigs, chickens, turkeys, quails,cats, dogs, mice, rats, rabbits or guinea pigs that have or may have themuscular disease. Administering the pharmaceutical composition accordingto the present disclosure to the individual may allow the diseases to beeffectively prevented or treated. The pharmaceutical compositionaccording to the present disclosure may be administered in combinationwith existing therapeutic agents.

The pharmaceutical compositions according to the present disclosure maycomprise further pharmaceutically acceptable additives. Thepharmaceutically acceptable additives may include starch, gelatinizedstarch, microcrystalline cellulose, lactose, povidone, colloidal silicondioxide, calcium hydrogen phosphate, lactose, mannitol, malt, arabianrubber, pregelatinized starch, corn starch, powdered cellulose,hydroxypropyl cellulose, Opadry, sodium starch glycolate, carnauba lead,synthetic aluminum silicate, stearic acid, magnesium stearate, aluminumstearate, calcium stearate, sucrose, dextrose, sorbitol, talc and thelike. The pharmaceutically acceptable additive according to the presentdisclosure may be preferably contained in a range of 0.1 parts by weightto 90 parts by weight with respect to a weight of the composition but isnot limited thereto.

In one aspect, the present disclosure relates to a pharmaceuticalcomposition for the prevention or treatment of muscle and fat losscaused by anticancer drugs, the composition ddining dimenhydrinate orcalcium pantothenate as active ingredients.

In one implementation, calcium pantothenate may comprise vitamins. Thevitamin may include a water-soluble vitamin selected from the groupconsisting of vitamin C, vitamin B1, vitamin B2, vitamin B6, vitamin H,vitamin PP or pro-vitamin B5 or mixtures thereof. The vitamin mayinclude a fat-soluble vitamin selected from the group consisting ofvitamin A, vitamin D, vitamin E, vitamin K1 or carotene or mixturesthereof. In a more preferred example, the vitamin may include vitamin B2(riboflavin, vit B2).

In one aspect, the present disclosure relates to a food composition forprevention or amelioration of a muscular disease, the compositioncomprising dimenhydrinate, harmol or calcium pantothenate.

In one implementation, calcium pantothenate may comprise vitamins. Thevitamin may include a water-soluble vitamin selected from the groupconsisting of vitamin C, vitamin B1, vitamin B2, vitamin B6, vitamin H,vitamin PP or pro-vitamin B5 or mixtures thereof. The vitamin mayinclude a fat-soluble vitamin selected from the group consisting ofvitamin A, vitamin D, vitamin E, vitamin K1 or carotene or mixturesthereof. In a more preferred example, the vitamin may include vitamin B2(riboflavin, vit B2).

In one implementation, each of dimenhydrinate, harmol and calciumpantothenate may be contained in a content range of from 250 nM to 20μM. More preferably, the harmol may be contained in a content range of500 nM to 10 μM and calcium pantothenate may be contained in a contentrange of 500 nM to 20 μM.

In one implementation, the pharmaceutical composition according to thepresent disclosure may comprise a combination of dimenhydrinate andharmol, a combination of dimenhydrinate and calcium pantothenate, acombination of harmol and calcium pantothenate, or a combination ofdimenhydrinate, harmol and calcium pantothenate as an active ingredient.In one example, the pharmaceutical composition according to the presentdisclosure may comprise combinations of dimenhydrinate, harmol and/orcalcium pantothenate as follows: dimenhydrinate 5 μM+harmol 250 nM,dimenhydrinate 5 μM+harmol 500 nM, dimenhydrinate 5 μM+calciumpantothenate 5 μM, dimenhydrinate 5 μM+calcium pantothenate 10 μM,dimenhydrinate 10 μM+harmol 250 nM, dimenhydrinate 10 μM+harmol 500 nM,dimenhydrinate 10 μM+calcium pantothenate 5 μM, dimenhydrinate 10μM+calcium pantothenate 10 μM, harmol 250 nM+calcium pantothenate 5 μM,harmol 250 nM+calcium pantothenate 10 μM, harmol 500 nM+calciumpantothenate 5 μM, harmol 500 nM+calcium pantothenate 10 μM,dimenhydrinate 5 μM+harmol 250 nM+calcium pantothenate 5 μM,dimenhydrinate 5 μM+harmol 250 nM+calcium pantothenate 10 μM,dimenhydrinate 10 μM+harmol 250 nM+calcium pantothenate 5 μM,dimenhydrinate 10 μM+harmol 250 nM+calcium pantothenate 10 μM,dimenhydrinate 5 μM+harmol 500 nM+calcium pantothenate 5 μM,dimenhydrinate 5 μM+harmol 500 nM+calcium pantothenate 10 μM,dimenhydrinate 10 μM+harmol 500 nM+calcium pantothenate 5 μM, anddimenhydrinate 10 μM+harmol 500 nM+calcium pantothenate 10 μM. In apreferable example, the pharmaceutical composition according to thepresent disclosure may comprise combinations of dimenhydrinate, harmoland/or calcium pantothenate as follows: dimenhydrinate 10 μM+calciumpantothenate 5 μM, dimenhydrinate 10 μM+calcium pantothenate 10 μM,harmol 250 nM+calcium pantothenate 5 μM, and harmol 250 nM+calciumpantothenate 10 μM. In one embodiment, dimenhydrinate, harmol andcalcium pantothenate according to the present disclosure showed asynergistic effect when they are contained in the composition in acombination manner rather than contained therein alone.

In one implementation, dimenhydrinate, harmol and/or calciumpantothenate in accordance with the present disclosure may increasemuscle mass or muscle strength via the promotion of myoblastproliferation and differentiation.

In one implementation, the muscular disease may include a musculardisease due to muscular dysfunction, muscle loss or muscle degenerationand may include one or more selected from a group consisting of atony,muscular atrophy, muscular dystrophy, myasthenia, cachexia andsarcopenia. More preferably, the muscular disease may include sarcopeniadue to aging or cancer.

When using the composition according to the present disclosure as a foodcomposition, the dimenhydrinate, harmol or calcium pantothenate may beadded as it is or may be used with other foods or food ingredients andmay be used suitably according to a conventional method. The compositionmay comprise food-acceptable food supplement additives in addition tothe active ingredient. The mixed amount of the active ingredient may beappropriately determined depending on the purpose of use (prevention,health or therapeutic treatment).

As used herein, the term “food supplement additive” means a componentthat may be added to a food in a supplementing manner and may be addedto prepare the health functional food of each formulation and may beselected by those skilled in the art as appropriate. Examples of thefood supplement additives may include flavors such as various nutrients,vitamins, minerals (electrolytes), synthetic and natural flavors,colorants and fillers, pectic acid and salts thereof, alginic acid andsalts thereof, organic acids, protective colloidal thickeners, pHadjusters, stabilizers, preservatives, glycerin, alcohols, carbonationagents used in carbonated drinks. The examples above do not limit thetype of the food supplement additive according to the presentdisclosure.

A health functional food may comprise the food composition according tothe present disclosure. The term “health functional food” as used in thepresent disclosure refers to food products prepared and processed in theform of tablets, capsules, powders, granules, liquids, and pills usingraw materials or ingredients having useful functions for the human body.Herein, the term ‘functional’ means to obtain a useful effect for healthpurposes such as nutrient control or physiological action on thestructure and function of the human body. Health functional foodsaccording to the present disclosure may be prepared by methods commonlyused in the art. In the preparation, the food may be prepared by addingthe raw materials and components commonly added in the art. In addition,the formulation of the health functional food may be prepared withoutlimitation as long as the formulation is recognized as a healthfunctional food. The food according to the present disclosure may beprepared in various forms of formulation. The food has the advantagethat unlike a general medicine, there is no side effect that may occurwhen taking the medicine for a long time. Due to its high portability,health functional foods in accordance with the present disclosure may betaken as supplements to enhance the effectiveness of anticancer drugs.

Further, there is no limit to the type of the health functional foods inwhich the composition according to the present disclosure may becontained. In addition, a composition comprising the dimenhydrinate,harmol or calcium pantothenate as an active ingredient according to thepresent disclosure may be mixed with other appropriate additives andother known additives that may be included in the health functional foodaccording to the choice of those skilled in the art. Examples of thefoods may include meat, sausages, bread, chocolate, candy, snacks,confectionery, pizza, ramen, other noodles, gum, dairy productscomprising ice cream, various soups, beverages, tea, drinks, alcoholicdrinks and vitamin complexes. The food may be prepared by adding thecomposition according to the present disclosure as a main ingredientinto tea, jelly and juice.

[Beat Mode]

The present disclosure is explained in more detail based on thefollowing example. However, the following example is intended to embodythe present disclosure, and thereby does not limit the presentdisclosure.

EXAMPLE 1 Identifying Effect of Application of Single Component

1-1. Identifying Effect of Dimenhydrinate Application

1-1-1. Identifying Promoting Effect of Myoblast Proliferation byDimenhydrinate Application

Mouse myoblast strain C2C12 was dispensed in 96-well plates at 1.5×10³cells/well, and then cultured in DMEM medium containing 10% fetal bovineserum (FBS) at 37° C. and 5% CO₂ for one day at a low density manner.Thereafter, the medium was replaced with DMEM medium containing 400 nMH₂O₂ and 0 nM, 250 nM, 500 nM, 1 μM, 2.5 μM, 5 μM, 10 μM or 20 μM ofdimenhydrinate (OC-501) respectively. At 16 hours since the replacement,the wells were treated with MTT reagent and then the mouse myoblaststrain C2C12 was incubated in the DMEM medium in a dark incubator for 3hours. After removing supernatant therefrom and applying 100 μl of DMSOto the well, the optical density (OD) was measured at 595 nm. Cells wereidentified using a microscope.

As a result, dimenhydrinate was found to promote myoblast proliferation(FIG. 1).

1-1-2. Identifying Promoting Effects of Myoblast Differentiation byDimenhydrinate Application

Mouse myoblast strain C2C12 was dispensed into 12-well plates at 0.7×10⁵cells/well and then cultured to a cell density of 70 to 80%. The cellswere then washed with PBS and then the medium was replaced with DMEMmedium (differentiation medium) containing 2% horse serum, 400 μM H₂O₂,and dimenhydrinate (OC-501) of 0 nM (DMSO), 500 nM, 5 μM, 10 μM or 20 μMrespectively. Differentiation of the myoblast was induced for 5 to 7days while the replacement of the medium occurred every other day. Afterthe differentiation, cells were identified using a microscope (4× and10× magnification), and cells were disrupted and then Western blotanalysis was performed using differentiation markers myogenin and myosinheavy chain (MHC) antibodies.

As a result, dimenhydrinate promoted differentiation of myoblast (FIG.2). The differentiation promotion increased especially at 5 μM ofdimenhydrinate (FIG. 3).

1-2. Identifying Effect of Harmol Application

1-2-1. Identifying Promoting Effect of Myoblast Proliferation by HarmolApplication

Mouse myoblast strain C2C12 was dispensed in 96-well plates at 1.5×10³cells/well, and then cultured in DMEM medium containing 10% fetal bovineserum (FBS) at 37° C. and 5% CO₂ for one day at a low density manner.Thereafter, the medium was replaced with DMEM medium containing 400 nMH₂O₂ and 0 nM, 250 nM, 500 nM, 1 μM, 2.5 μM, 5 μM, 10 μM or 20 μM ofharmol (OC-503) respectively. At 16 hours since the replacement, thewells were treated with MTT reagent and then the mouse myoblast strainC2C12 was incubated in the DMEM medium in a dark incubator for 3 hours.After removing supernatant therefrom and applying 100 μl of DMSO to thewell, the optical density (OD) was measured at 595 nm. Cells wereidentified using a microscope.

As a result, harmol was found not to promote myoblast proliferation(FIG. 4).

1-2-2. Identifying Promoting Effects of Myoblast Differentiation byHarmol Application

Mouse myoblast strain C2C12 was dispensed into 12-well plates at 0.7×10⁵cells/well and then cultured to a cell density of 70 to 80%. The cellswere then washed with PBS and then the medium was replaced with DMEMmedium (differentiation medium) containing 2% horse serum, 400 μM H₂O₂,and harmol (OC-503) of 0 nM (DMSO), 500 nM, 1 μM, 2.5 μM, 5 μM, or 10 μMrespectively. Differentiation of the myoblast was induced for 5 to 7days while the replacement of the medium occurred every other day. Afterthe differentiation, cells were identified using a microscope, and cellswere disrupted, and then Western blot analysis was performed usingdifferentiation markers myogenin and myosin heavy chain (MHC)antibodies.

As a result, harmol promoted differentiation of myoblast (FIG. 5). Thedifferentiation promotion increased especially at 5 μM and 10 μM ofharmol (FIG. 6).

1-3. Identifying Effect of Calcium Pantothenate Application

1-3-1. Identifying Promoting Effects of Myoblast Proliferation byCalcium Pantothenate Application

Mouse myoblast strain C2C12 was dispensed in 96-well plates at 1.5×10³cells/well, and then cultured in DMEM medium containing 10% fetal bovineserum (FBS) at 37° C. and 5% CO₂ for one day at a low density manner.Thereafter, the medium was replaced with DMEM medium containing 400 nMH₂O₂ and 0 nM, 250 nM, 500 nM, 1 μM, 2.5 μM, 5 μM, 10 μM or 20 μM ofcalcium pantothenate (OC-504) respectively. At 16 hours since thereplacement, the wells were treated with MTT reagent and then the mousemyoblast strain C2C12 was incubated in the DMEM medium in a darkincubator for 3 hours. After removing supernatant therefrom and applying100 μl of DMSO to the well, the optical density (OD) was measured at 595nm. Cells were identified using a microscope.

As a result, calcium pantothenate was found not to promote myoblastproliferation (FIG. 7).

1-3-2. Identifying Promoting Effects of Myoblast Differentiation byCalcium Pantothenate Application

Mouse myoblast strain C2C12 was dispensed into 12-well plates at 0.7×10⁵cells/well and then cultured to a cell density of 70 to 80%. The cellswere then washed with PBS and then the medium was replaced with DMEMmedium (differentiation medium) containing 2% horse serum, 400 μM H₂O₂,and calcium pantothenate (OC-504) of 0 nM (DMSO), 500 nM, 2.5 μM, 5 μM,10 μM or 20 μM respectively. Differentiation of the myoblast was inducedfor 5 to 7 days while the replacement of the medium occurred every otherday. After the differentiation, cells were identified using a microscope(4× and 10× magnification), and cells were disrupted, and then Westernblot analysis was performed using differentiation markers myogenin andmyosin heavy chain (MHC) antibodies.

As a result, calcium pantothenate promoted differentiation of myoblast(FIG. 8). The differentiation promotion increased especially at 5 μM and10 μM of calcium pantothenate (FIG. 9).

EXAMPLE 2 Identifying Effect of Application of Combination of Components

2-1. Cytotoxicity Identification

Mouse myoblast strain C2C12 was dispensed in 96-well plates at 1.5×10³cells/well. A combination of dimenhydrinate (OC-501), harmol (OC-503)and calcium pantothenate (OC-504) was applied thereto. Then, the mousemyoblast strain C2C12 was cultured in DMEM medium containing 10% fetalbovine serum (FBS) and each of combinations of OC-501 5 μM+OC-503 250nM, OC-501 5 μM+OC-503 500 nM, OC-501 5 μM+OC-504 5 μM, OC-501 5μM+OC-504 10 μM, OC-501 10 μM+OC-503 250 nM, OC-501 10 μM+OC-503 500 nM,OC-501 10 μM+OC-504 5 μM, OC-501 10 μM+OC-504 10 μM, OC-503 250nM+OC-504 5 μM, OC-503 250 nM+OC-504 10 μM, OC-503 500 nM+OC-504 5 μM,OC-503 500 μM+OC-504 10 μM, OC-501 5 μM+OC-503 250 nM+OC-504 5 μM,OC-501 5 μM+OC-503 250 nM+OC-504 10 μM, OC-501 10 μM+OC-503 250nM+OC-504 5 μM, OC-501 10 μM+OC-503 250 nM+OC-504 10 μM, OC-501 5μM+OC-503 500 nM+OC-504 5 μM, OC-501 5 μM+OC-503 500 nM+OC-504 10 μM,OC-501 10 μM+OC-503 500 nM+OC-504 5 μM, and OC-501 10 μM+OC-503 500nM+OC-504 10 μM. At 24, 48, and 72 hours since the application, thewells were treated with MTT reagent and then the mouse myoblast strainC2C12 was incubated in the DMEM medium in a dark incubator for 3 hours.After removing supernatant therefrom and applying 100 μl of DMSO to eachwell, the optical density (OD) was measured at 595 nm to identifycytotoxicity. The experiment was performed three times.

As a result, the combination of dimenhydrinate (OC-501), harmol (OC-503)and calcium pantothenate (OC-504) according to the present disclosureshowed no cytotoxicity (FIG. 10).

2-2. Identifying Promoting Effects of Myoblast Differentiation byCombination Application

Mouse myoblast strain C2C12 was dispensed in 96-well plates at 1.5×10³cells/well, and then cultured in DMEM medium containing 10% fetal bovineserum (FBS) at 37° C. and 5% CO₂ for one day at a low density manner.Thereafter, the medium was replaced with DMEM medium containing 400 μMH₂O₂ and each of following combinations of dimenhydrinate (OC-501),harmol (OC-503), and calcium pantothenate (OC-504): OC-501 5 μM+OC-503250 nM, OC-501 5 μM+OC-503 500 nM, OC-501 5 μM+OC-504 5 μM, OC-501 5μM+OC-504 10 μM, OC-501 10 μM+OC-503 250 nM, OC-501 10 μM+OC-503 500 nM,OC-501 10 μM+OC-504 5 μM, OC-501 10 μM+OC-504 10 μM, OC-503 250nM+OC-504 5 μM, OC-503 250 nM+OC-504 10 μM, OC-503 500 nM+OC-504 5 μM,OC-503 500 nM+OC-504 10 μM, OC-501 5 μM+OC-503 250 nM+OC-504 5 μM,OC-501 5 μM+OC-503 250 nM+OC-504 10 μM, OC-501 10 μM+OC-503 250nM+OC-504 5 μM, OC-501 10 μM+OC-503 250 nM+OC-504 10 μM, OC-501 5μM+OC-503 500 nM+OC-504 5 μM, OC-501 5 μM+OC-503 500 nM+OC-504 10 μM,OC-501 10 μM+OC-503 500 nM+OC-504 5 μM, and OC-501 10 μM+OC-503 500nM+OC-504 10 μM. At 16 hours since the replacement, the wells weretreated with MTT reagent and then the mouse myoblast strain C2C12 wasincubated in the DMEM medium in a dark incubator for 3 hours. Afterremoving supernatant therefrom and applying 100 μl of DMSO to the well,the optical density (OD) was measured at 595 nm. Cells were identifiedusing a microscope.

As a result, it was confirmed that the combinations of dimenhydrinate(OC-501) 10 μM and harmol (OC-503) 500 nM, dimenhydrinate (OC-501) 10 μMand calcium pantothenate (OC-504) 5 dimenhydrinate (OC-501) 10 μM andcalcium pantothenate (OC-504) 10 μM, dimenhydrinate (OC-501) 5 μM,harmol (OC-503) 500 nM and calcium pantothenate (OC-504) 10 μM,dimenhydrinate (OC-501) 10 μM, harmol (OC-503) 500 nM and calciumpantothenate (OC-504) 5 μM, dimenhydrinate (OC-501) 10 μM, and harmol(OC-503) 500 nM and calcium pantothenate (OC-504) 10 μM significantlyincreased myoblast proliferation (FIG. 11 to FIG. 13).

2-3. Identifying Promoting Effects of Myoblast Differentiation byCombination Application

Mouse myoblast strain C2C12 was dispensed into 12-well plates at 0.7×10⁵cells/well and then cultured to a cell density of 70 to 80%. The cellswere then washed with PBS and then the medium was replaced with DMEMmedium (differentiation medium) containing 2% horse serum, 400 μM H₂O₂,and each of following combinations of dimenhydrinate (OC-501), harmol(OC-503), and calcium pantothenate (OC-504): OC-501 5 μM+OC-503 250 nM,OC-501 5 μM+OC-503 500 nM, OC-501 5 μM+OC-504 5 μM, OC-501 5 μM+OC-50410 μM, OC-501 10 μM+OC-503 250 nM, OC-501 10 μM+OC-503 500 nM, OC-501 10μM+OC-504 5 μM, OC-501 10 μM+OC-504 10 μM, OC-503 250 nM+OC-504 5 μM,OC-503 250 nM+OC-504 10 μM, OC-503 500 nM+OC-504 5 μM, OC-503 500nM+OC-504 10 μM, OC-501 5 μM+OC-503 250 nM+OC-504 5 μM, OC-501 5μM+OC-503 250 nM+OC-504 10 μM, OC-501 10 μM+OC-503 250 nM+OC-504 5 μM,OC-501 10 μM+OC-503 250 nM+OC-504 10 μM, OC-501 5 μM+OC-503 500nM+OC-504 5 μM, OC-501 5 μM+OC-503 500 nM+OC-504 10 μM, OC-501 10μM+OC-503 500 nM+OC-504 5 μM, and OC-501 10 μM+OC-503 500 nM+OC-504 10μM. Differentiation of the myoblast was induced for 5 to 7 days whilethe replacement of the medium occurred every other day. After thedifferentiation, cells were identified using a microscope (4× and 10×magnification), and cells were disrupted, and then Western blot analysiswas performed using differentiation markers myogenin and myosin heavychain (MHC) antibodies.

As a result, a combination of dimenhydrinate and calcium pantothenate,and a combination of dimenhydrinate and harmol facilitateddifferentiation of myoblasts (FIG. 14). In particular, the promotion ofdifferentiation thereof was more markedly increased when applying OC-50110 μM+OC-504 5 μM, OC-501 10 μM+OC-504 10 μM, OC-503 250 nM+OC-504 5 μM,and OC-503 250 nM+OC-504 10 μM (FIG. 15).

EXAMPLE 3 Identifying Effect by Combination of Dimenhydrinate andCalcium Pantothenate

3-1. Identifying Promoting Effects of Myoblast Differentiation byCombination of Dimenhydrinate and Calcium Pantothenate

Mesenchymal stem cells were isolated on day 3 after cobratoxin wasinserted into the tibialis anterior muscle of the mouse. Two days afterthe separation, 10 μM of dimenhydrinate (OC-501) and 5 μM of calciumpantothenate (OC-504) were administered individually or in combination.West blot analysis was performed using differentiation markers PAX7(paired box protein-7) and MYF5 (Myogenic factor 5) antibodies. Afterthe differentiation, cells were identified using a microscope (4× and10× magnification).

As a result, 4 days after the application, the expression of PAX7 wasincreased when applying the calcium pantothenate-treated group and whenapplying the combination of dimenhydrinate and calcium pantothenate(FIG. 16).

3-2. Identifying Muscle Regeneration Effect by Combination ofDimenhydrinate and Calcium Pantothenate

At 3 days after inserting cobratoxin into the tibialis anterior muscleof the mouse, each of dimenhydrinate (OC-501) and calcium pantothenate(OC-504) was applied at 30 mpk (mg/kg) for 3 days, and dimenhydrinate(OC-501) and calcium pantothenate (OC-504) were co-administered suchthat each content is 15 or 30 mpk (mg/kg) for 3 days. The next day themice were sacrificed to identify the extent of muscle regeneration.

As a result, in control mice, myoblasts (dark purple) were just about tostart differentiation. In the application of the combination ofdimenhydrinate (OC-501) and calcium pantothenate (OC-504), muscle (pink)regeneration was already completed (FIG. 17).

3-3. Identifying Early Recovery of Muscle Fibers by Combination ofDimenhydrinate and Calcium Pantothenate

At 3 days after inserting not cobratoxin but cardiotoxin into thetibialis anterior muscle of the mouse, each of dimenhydrinate (OC-501)and calcium pantothenate (OC-504) was applied at 30 mpk (mg/kg), anddimenhydrinate (OC-501) and calcium pantothenate (OC-504) wereco-administered such that each content is 15 or 30 mpk (mg/kg). Then,the muscle fiber was identified.

As a result, in the control group, the muscle fibers contracted andmostly showed a size of 200 μm² or smaller. In the application of OC-501and OC-504 alone and in combination, the muscle fiber size was wellsparred (FIG. 18).

3-4. Identifying Effect of Combination of Dimenhydrinate and CalciumPantothenate on Cancer-Associated Muscle and Fat Reduction

Cancer-associated sarcopenia was induced by administering 5-FU(5-fluorouracil) as an anticancer agent to mice transplanted withcolorectal cancer cells CT26. Further, after the colon cancer celltransplantation, dimenhydrinate (OC-501) and calcium pantothenate(OC-504) were applied thereto alone or in combination. MRI was measuredevery week to determine muscle and fat changes in OC-501 and 504 aloneand combination-treated groups (FIG. 19).

As a result, sarcopenia was hardly induced in the control micetransplanted with only cancer cells. The muscle amount was decreased byabout 40% and the fat was decreased by 95% when the anticancer drug wasadministered. The muscle mass and fat mass were increased in the groupstreated with dimenhydrinate (OC-501) and calcium pantothenate (OC-504)alone or in combination (FIG. 20). In particular, the combination of 20mpk of dimenhydrinate (OC-501) and 40 mpk of calcium pantothenate(OC-504) recovered muscle and fat levels to a similar degree to thecontrol group.

The invention claimed is:
 1. A composition for treating atony, muscularatrophy, muscular dystrophy, myasthenia, cachexia or sarcopenia, ormuscle or fat loss caused by administration of an anticancer drug, thecomposition comprising a combination of dimenhydrinate and calciumpantothenate, wherein the dimenhydrinate is represented by the followingChemical Formula 1:

and wherein the calcium pantothenate is represented by the followingChemical Formula 3:


2. The composition of claim 1, wherein the sarcopenia is caused by agingor cancer.
 3. The composition of claim 1, further comprising awater-soluble vitamin selected from the group consisting of vitamin C,vitamin B1, vitamin B2, vitamin B6, vitamin H, vitamin PP, pro-vitaminB5 and mixtures thereof.
 4. The composition of claim 1, furthercomprising a fat-soluble vitamin selected from the group consisting ofvitamin A, vitamin D, vitamin E, vitamin K1, carotene and mixturesthereof.
 5. A composition comprising a combination of dimenhydrinate andharmol, a combination of dimenhydrinate and calcium pantothenate, acombination of harmol and calcium pantothenate, or a combination ofdimenhydrinate, harmol and calcium pantothenate.
 6. The composition ofclaim 1, wherein the sarcopenia is caused by aging of cancer.
 7. Thecomposition of claim 5, further comprising a water-soluble vitaminselected from the group consisting of vitamin C, vitamin B1, vitamin B2,vitamin B6, vitamin H, vitamin PP, pro-vitamin B5 and mixtures thereof.8. The composition of claim 5, further comprising a fat-soluble vitaminselected from the group consisting of vitamin A, vitamin D, vitamin E,vitamin K1, carotene and mixtures thereof.
 9. A method for treatingatony, muscular atrophy, muscular dystrophy, myasthenia, cachexia orsarcopenia, or muscle or fat loss caused by administration of ananticancer drug, comprising administering to a subject in need thereof acomposition comprising a combination of dimenhydrinate- and calciumpantothenate, wherein the dimenhydrinate is represented by the followingChemical Formula 1:

and wherein the calcium pantothenate is represented by the followingChemical Formula 3:


10. The method of claim 9, wherein the sarcopenia is caused by aging orcancer.
 11. The method of claim 9, wherein the composition furthercomprises a water-soluble vitamin selected from the group consisting ofvitamin C, vitamin B1, vitamin B2, vitamin B6, vitamin H, vitamin PP,pro-vitamin B5 and mixtures thereof.
 12. The method of claim 9, whereinthe composition further comprises a fat-soluble vitamin selected fromthe group consisting of vitamin A, vitamin D, vitamin E, vitamin K1,carotene and mixtures thereof.
 13. A method for treating atony, muscularatrophy, muscular dystrophy, myasthenia, cachexia or sarcopenia, ormuscle or fat loss caused by administration of an anticancer drug,comprising administering to a subject in need thereof a compositioncomprising a combination of dimenhydrinate and harmol, a combination ofdimenhydrinate and calcium pantothenate, a combination of harmol andcalcium pantothenate, or a combination of dimenhydrinate, harmol andcalcium pantothenate.
 14. The method of claim 13, wherein the sarcopeniais caused by aging or cancer.
 15. The method of claim 13, wherein thecomposition further comprises a water-soluble vitamin selected from thegroup consisting of vitamin C, vitamin B1, vitamin B2, vitamin B6,vitamin H, vitamin PP, pro-vitamin B5 and mixtures thereof.
 16. Themethod of claim 13, wherein the composition further comprises afat-soluble vitamin selected from the group consisting of vitamin A,vitamin D, vitamin E, vitamin K1, carotene and mixtures thereof.